Studies of chemical disposition are designed to provide both applied knowledge of the fate of chemicals in the intact animal in support of toxicity tests conducted by the National Toxicology Program and basic knowledge of mechanisms of chemical toxicity. Each study is designed to address those physical and chemical properties unique to the compounds studied as well as to provide data which will permit structural characterization of the respective chemical class. Each study is also designed to address the impact of one or more factors such as dose, age, sex or route of exposure on the toxicity of the chemical(s) studied and the significance of this data to assessments of human health risks. Studies conducted during the current year have addressed the fate and mechanisms of toxicity of 2-methylimidazole (2-MI) a synthetic intermediate widely used in the synthesis of pharmaceuticals, agricultural chemicals, dyes and in rubber manufacturing and the metabolism of model compounds by transgenic animals. Studies of 2-MI indicate that it is rapidly absorbed from the gastrointestinal tracts of both rats and mice and rapidly excreted, primarily in urine. Metabolism is not extensive and 70% of the material excreted is parent compound. It does, however, induce increased levels of glucuronosyl- transferase that account for the more rapid clearance of thyroid hormones. Studies of xenobiotic metabolism by transgenic strains of mice are designed to confirm the utility of these strains as models for detection of carcinogenic agents. Three strains of transgenic mice, TG.AC, P-53 knockout and COX2, are being examined for their capacity to metabolize three xenobiotics, benzene, ethoxyquin and methacrylonitrile. Studies of these compounds offer the opportunity to examine the primary metabolic pathways and include several P-450 reactions as well as the primary phase two pathways.